The overall goal of this Program is to conduct investigations into the molecular biology and biochemistry of signal transduction events leading to lymphocyte development, activation, and apoptosis. Recent work from many laboratories has demonstrated that the spatial and temporal organization of multimolecular signaling complexes plays a critical role in the regulation of each of these cellular processes. Accordingly, each project in this Program will address, in some way, the role of intermolecular interactions in the regulation of lymphocyte function. Two projects will focus on T lymphocytes and two projects will address related questions in B cells. Project 1 describes experiments examining the structure/function relationships of the adapter protein SLP-76 as a regulator of T cell development and T cell activation. The second project will investigate how pleckstrin, a highly abundant lymphocyte protein, impacts cytoskeletal reorganization. The third and fourth projects of this Program will focus on B-lymphocytes. Project 3 will investigate how the B cell antigen receptor transduces signals when not bound by ligand while the fourth project will address the role of Notch proteins in B cell development and apoptosis. The four projects bring together four established investigators, each with thriving individual research programs who wish to formalize their interactions through this joint effort. The Program will be supported by an administrative core and two scientific cores. The first scientific core will assist in analysis of in vivo structure/function relationships of critical signaling molecules using a retroviral transduction approach into bone marrow progenitor cells. The second scientific core, led by a fifth investigator associated with our Program, will provide expertise in image analysis, assisting each project in visualizing intermolecular complexes. We anticipate that our collective efforts will provide new insights into lymphocyte biology and will hopefully provide clues for novel therapeutic interventions to modulate immune cell function.